Startseite Promoter methylation levels of RASSF1 and ATIC genes are associated with lung cancer in Iranian patients
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Promoter methylation levels of RASSF1 and ATIC genes are associated with lung cancer in Iranian patients

  • Mahsa Mashayekhi , Milad Asadi , Shahriar Hashemzadeh , Amir Vahedi , Dariush Shanehbandi , Ahmad Faris Al-Omar , Morteza Akbari und Mortaza Raeisi EMAIL logo
Veröffentlicht/Copyright: 2. Januar 2023
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Abstract

Objectives

Epigenetic alterations like methylation of tumor suppressor genes or oncogenes, in respiratory epithelium have been associated with lung cancer. Hypermethylation of genes promoter is an epigenetic event, and is responsible to tumor suppressor genes inactivation as well as oncogenes activation. This study aimed to assess the role of methylation status in promoter of RASSF1 and ATIC genes their potential implication in the pathogenesis of lung tumor in Iranian patients.

Methods

In this study, we collected 100 tissue samples (50 lung cancer tissues and 50 adjacent non-cancerous lung tissues) from Iranian lung cancer patients. The genomic DNA was extracted, and methylation status of both RASSF1 and ATIC genes was investigated by methylation-sensitive high-resolution melting (MS-HRM) assay technique and Real-Time PCR. Cancer Genome Atlas (TCGA) dataset was also analyzed for further validation of the gene’s methylation.

Results

Methylation of RASSF1 gene promoter was significantly higher in lung tumor tissues. However, promoter methylation levels of ATIC gene was significantly lower in lung tumor tissues. These results were additionally confirmed by TCGA analysis. Promoter methylation of both RASSF1 and ATIC genes was significantly associated with lymph node metastasis, and clinical stage of lung cancer. The receiver operating characteristic (ROC) curve analysis indicated a high accuracy of promoter methylation in these genes as a diagnostic biomarker for lung cancer.

Conclusions

Methylation levels of both RASSF1 and ATIC genes promoters were associated with lung cancer pathogenesis in Iranian population, and may be a suitable biomarker for diagnosis and prognosis of lung cancer in early stage of tumorigenesis.


Corresponding author: Mortaza Raeisi, Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, E-mail:

  1. Research funding: This work was supported by Tabriz University of Medical Sciences.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The local Institutional Review Board deemed the study exempt from review.

References

1. Zarredar, H, Farajnia, S, Ansarin, K, Baradaran, B, Aria, M, Asadi, M. Synergistic effect of novel EGFR inhibitor AZD8931 and p38α siRNA in lung adenocarcinoma cancer cells. Anti Cancer Agents Med Chem 2019;19:638–44. https://doi.org/10.2174/1871520619666190301125203.Suche in Google Scholar PubMed

2. Siegel, R, Miller, K, Fuchs, H, Jemal, A. Cancer statistics. CA Cancer J Clin 2021;71:7–33. https://doi.org/10.3322/caac.21654.Suche in Google Scholar PubMed

3. Shanehbandi, D, Asadi, M, Seyedrezazadeh, E, Zafari, V, Shekari, N, Akbari, M, et al.. MicroRNA-based biomarkers in lung cancer: recent advances and potential applications. Curr Mol Med 2022. https://doi.org/10.2174/2772432817666220520085719 [Epub ahead of print].10.2174/2772432817666220520085719Suche in Google Scholar PubMed

4. Bouras, E, Karakioulaki, M, Bougioukas, KI, Aivaliotis, M, Tzimagiorgis, G, Chourdakis, M. Gene promoter methylation and cancer: an umbrella review. Gene 2019;710:333–40. https://doi.org/10.1016/j.gene.2019.06.023.Suche in Google Scholar PubMed

5. Castro, M, Grau, L, Puerta, P, Gimenez, L, Venditti, J, Quadrelli, S, et al.. Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in lung cancer. J Transl Med 2010;8:1–11. https://doi.org/10.1186/1479-5876-8-86.Suche in Google Scholar PubMed PubMed Central

6. Kuo, LT, Lu, HY, Lee, CC, Tsai, JC, Lai, HS, Tseng, HM, et al.. Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in oligodendroglial tumors. Cancer Med 2016;5:1830–9. https://doi.org/10.1002/cam4.762.Suche in Google Scholar PubMed PubMed Central

7. Hu, YC, Sidransky, D, Ahrendt, SA. Molecular detection approaches for smoking associated tumors. Oncogene 2002;21:7289–97. https://doi.org/10.1038/sj.onc.1205805.Suche in Google Scholar PubMed

8. Amato, E, Barbi, S, Fassan, M, Luchini, C, Vicentini, C, Brunelli, M, et al.. RASSF1 tumor suppressor gene in pancreatic ductal adenocarcinoma: correlation of expression, chromosomal status and epigenetic changes. BMC Cancer 2016;16:1–9. https://doi.org/10.1186/s12885-016-2048-0.Suche in Google Scholar PubMed PubMed Central

9. Arnette, C, Efimova, N, Zhu, X, Clark, GJ, Kaverina, I. Microtubule segment stabilization by RASSF1A is required for proper microtubule dynamics and Golgi integrity. Mol Biol Cell 2014;25:800–10. https://doi.org/10.1091/mbc.e13-07-0374.Suche in Google Scholar

10. Fu, L, Zhang, S. RASSF1A promotes apoptosis and suppresses the proliferation of ovarian cancer cells. Int J Mol Med 2014;33:1153–60. https://doi.org/10.3892/ijmm.2014.1671.Suche in Google Scholar PubMed

11. Guo, W, Cui, L, Wang, C, Guo, Y, Shen, S, Kuang, G, et al.. Decreased expression of RASSF1A and up-regulation of RASSF1C is associated with esophageal squamous cell carcinoma. Clin Exp Metastasis 2014;31:521–33. https://doi.org/10.1007/s10585-014-9646-5.Suche in Google Scholar PubMed

12. Grawenda, A, O’neill, E. Clinical utility of RASSF1A methylation in human malignancies. Br J Cancer 2015;113:372–81. https://doi.org/10.1038/bjc.2015.221.Suche in Google Scholar PubMed PubMed Central

13. Donninger, H, Clark, JA, Monaghan, MK, Schmidt, ML, Vos, M, Clark, GJ. Cell cycle restriction is more important than apoptosis induction for RASSF1A protein tumor suppression. J Biol Chem 2014;289:31287–95. https://doi.org/10.1074/jbc.m114.609537.Suche in Google Scholar PubMed PubMed Central

14. Liu, L, Kron, KJ, Pethe, VV, Demetrashvili, N, Nesbitt, ME, Trachtenberg, J, et al.. Association of tissue promoter methylation levels of APC, TGFβ2, HOXD3 and RASSF1A with prostate cancer progression. Int J Cancer 2011;129:2454–62. https://doi.org/10.1002/ijc.25908.Suche in Google Scholar PubMed

15. Fischer, JR, Ohnmacht, U, Rieger, N, Zemaitis, M, Stoffregen, C, Manegold, C, et al.. Prognostic significance of RASSF1A promoter methylation on survival of non-small cell lung cancer patients treated with gemcitabine. Lung Cancer 2007;56:115–23. https://doi.org/10.1016/j.lungcan.2006.11.016.Suche in Google Scholar PubMed

16. Chan, CY, Zhao, H, Pugh, RJ, Pedley, AM, French, J, Jones, SA, et al.. Purinosome formation as a function of the cell cycle. Proc Natl Acad Sci USA 2015;112:1368–73. https://doi.org/10.1073/pnas.1423009112.Suche in Google Scholar PubMed PubMed Central

17. Liu, X, Chhipa, RR, Pooya, S, Wortman, M, Yachyshin, S, Chow, LM, et al.. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc Natl Acad Sci 2014;111:E435–44. https://doi.org/10.1073/pnas.1311121111.Suche in Google Scholar PubMed PubMed Central

18. Beardsley, GP, Rayl, EA, Gunn, K, Moroson, BA, Seow, H, Anderson, KS, et al.. Structure and functional relationships in human pur H. In: Purine and pyrimidine metabolism in man IX. Boston, MA: Springer; 1998:221–6 pp.10.1007/978-1-4615-5381-6_43Suche in Google Scholar PubMed

19. Zhang, H, Xia, P, Liu, J, Chen, Z, Ma, W, Yuan, Y. ATIC inhibits autophagy in hepatocellular cancer through the AKT/FOXO3 pathway and serves as a prognostic signature for modeling patient survival. Int J Biol Sci 2021;17:4442. https://doi.org/10.7150/ijbs.65669.Suche in Google Scholar PubMed PubMed Central

20. Li, M, Jin, C, Xu, M, Zhou, L, Li, D, Yin, Y. Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6 K1 signaling. Cell Commun Signal 2017;15:1–14. https://doi.org/10.1186/s12964-017-0208-8.Suche in Google Scholar PubMed PubMed Central

21. Zarredar, H, Pashapour, S, Farajnia, S, Ansarin, K, Baradaran, B, Ahmadzadeh, V, et al.. Targeting the KRAS, p38α, and NF-κB in lung adenocarcinoma cancer cells: the effect of combining RNA interferences with a chemical inhibitor. J Cell Biochem 2019;120:10670–7. https://doi.org/10.1002/jcb.28357.Suche in Google Scholar PubMed

22. Delmonico, L, Costa, MASM, Gomes, RJ, Vieira, PDO, Da Silva, ABP, Fournier, MV, et al.. Methylation profiling in promoter sequences of ATM and CDKN2A (p14ARF/p16INK4a) genes in blood and cfDNA from women with impalpable breast lesions. Oncol Lett 2020;19:3003–10. https://doi.org/10.3892/ol.2020.11382.Suche in Google Scholar PubMed PubMed Central

23. Krasteva, ME, Antov, GG, Gospodinova, ZI, Angelova, SG, Nacheva, MB, Georgieva, EI, et al.. Aberrant promoter methylation in p53 and ATM genes was not associated with sporadic breast carcinogenesis in Bulgarian patients. J BioSci Biotechnol 2014;3:105–9.Suche in Google Scholar

24. Ramirez, J, Taron, M, Balana, C, Sarries, C, Mendez, P, de Aguirre, I, et al.. Serum DNA as a tool for cancer patient management. Rocz Akad Med Bialymst 2003;48:34–41.Suche in Google Scholar

25. Battagli, C, Uzzo, RG, Dulaimi, E, Ibanez de Caceres, I, Krassenstein, R, Al-Saleem, T, et al.. Promoter hypermethylation of tumor suppressor genes in urine from kidney cancer patients. Cancer Res 2003;63:8695–9.Suche in Google Scholar

26. Dulaimi, E, Hillinck, J, de Caceres, II, Al-Saleem, T, Cairns, P. Tumor suppressor gene promoter hypermethylation in serum of breast cancer patients. Clin Cancer Res 2004;10:6189–93. https://doi.org/10.1158/1078-0432.ccr-04-0597.Suche in Google Scholar

27. Wang, J, Lee, JJ, Wang, L, Liu, DD, Lu, C, Fan, Y-H, et al.. Value of p16 INK4a and RASSF1A promoter hypermethylation in prognosis of patients with resectable non–small cell lung cancer. Clin Cancer Res 2004;10:6119–25. https://doi.org/10.1158/1078-0432.ccr-04-0652.Suche in Google Scholar

28. Volodko, N, Salla, M, Zare, A, Abulghasem, E-A, Vincent, K, Benesch, MG, et al.. RASSF1A Site-specific methylation hotspots in cancer and correlation with RASSF1C and MOAP-1. Cancers 2016;8:55. https://doi.org/10.3390/cancers8060055.Suche in Google Scholar PubMed PubMed Central

29. Burbee, DG, Forgacs, E, Zöchbauer-Müller, S, Shivakumar, L, Fong, K, Gao, B, et al.. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 2001;93:691–9. https://doi.org/10.1093/jnci/93.9.691.Suche in Google Scholar PubMed PubMed Central

30. Fraser, HB, Lam, LL, Neumann, SM, Kobor, MS. Population-specificity of human DNA methylation. Genome Biol 2012;13:R8. https://doi.org/10.1186/gb-2012-13-2-r8.Suche in Google Scholar PubMed PubMed Central

Received: 2022-01-14
Accepted: 2022-12-11
Published Online: 2023-01-02

© 2022 Walter de Gruyter GmbH, Berlin/Boston

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